The EGFR/HER2 signaling network emerges as an effective therapeutic target in lung, colon, pancreas, head/neck and breast tumors. Over the last five years our laboratory studied the HER2 subtype of breast cancer and highlighted functional features, which collectively confer robustness (outcome reproducibility) and plasticity (secondary resistance) to the HER2 network [Citri and Yarden (2006) Nature Reviews Molec. Cell Biol.]. Alongside, we demonstrated several novel strategies capable of intercepting the EGF-to-EGFR/HER2 pathway (e.g., antibody combinations, soluble chimeric receptors and anti-ligand antibodies). Our current working hypothesis assumes that the EGFR/HER2 network plays a driving role not only in the HER2 subtype of breast cancer, but also in the similarly aggressive basal-like subtype. Consistent with this proposition, EGFR is almost ubiquitously expressed in basal-like tumors, and according to a recent comprehensive study of expression profiles, almost all tumors of this class express EGFR-associated, poor prognostic signatures. If validated, the working model predicts that anti-EGFR/HER2 therapies may have broader than expected value in breast cancer therapy. Hence, over the next five years we will focus on both the HER2 and the basal-like subtypes and address collaborating biochemical mechanisms, as well as prospects for new targeted therapies. Our first task entails construction of relevant cellular model systems, expressing either an active form of EGFR, or an amplified HER2, on the genetic background of normal basal-like cells. In the next step, we will study the respective three-dimensional spheroids by extracting both genetic and proteomic signatures, as well as by introducing collaborative genetic events. For example, loss of expression of p53, PTEN, BRCA1 and Rb (basal-like models) and co-amplified, chromosome 17 genes (HER2 models). Our therapeutic task will extend the experimental armamentarium by developing EGFR/HER2-specific aptamers and testing them in tumor-bearing animals, either side by side or in combination with decoy receptors and other novel therapies we established over the last five years.